Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.W., C.F.P., M.J.J.R.); Interdisciplinary Biological Sciences Program (A.W.A.) and Department of Pediatrics, Arkansas Children's Nutrition Center (K.E.M., J.-R.C.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (L.J.S.).
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana (J.W., C.F.P., M.J.J.R.); Interdisciplinary Biological Sciences Program (A.W.A.) and Department of Pediatrics, Arkansas Children's Nutrition Center (K.E.M., J.-R.C.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (L.J.S.)
J Pharmacol Exp Ther. 2018 Jul;366(1):46-57. doi: 10.1124/jpet.117.247262. Epub 2018 Apr 13.
Chronic alcohol consumption increases bone resorption and decreases bone formation. A major component of ethanol (EtOH) pathology in bone is the generation of excess reactive oxygen species (ROS). The ROS-generating NADPH oxidase-4 (NOX4) is proposed to drive much of the EtOH-induced suppression of bone formation. Here, 13-week-old male wild-type (WT) and NOX4 mice were pair fed (PF) a high-fat (35%), Lieber-DeCarli liquid diet with or without EtOH at 30% of their total calories for 12 weeks. Micro-computed tomography analysis demonstrated significant decreases in trabecular bone volume/total volume (BV/TV) percentage and cortical thickness in WT, EtOH-fed mice compared with PF controls. EtOH-fed NOX4 mice also displayed decreased trabecular BV/TV and trabecular number compared with PF ( < 0.05). However, NOX4 mice were protected against EtOH-induced decreases in cortical thickness ( < 0.05) and decreases in collagen1 and osteocalcin mRNA expression in cortical bone ( < 0.05). In WT and NOX4 vertebral bone, EtOH suppressed expression of Wnt signaling components that promote osteoblast maturation. A role for NOX4 in EtOH inhibition of osteoblast differentiation was further demonstrated by protection against EtOH inhibition of osteoblastogenesis in ex vivo bone marrow cultures from NOX4, but not p47 mice lacking active NADPH oxidase-2. However, bone marrow cultures from NOX4 mice formed fewer osteoblastic colonies compared with WT cultures ( < 0.05), suggesting a role for NOX4 in the maintenance of mesenchymal progenitor cell populations. These data suggest that NOX4 deletion is partially protective against EtOH effects on osteoblast differentiation, but may predispose bone to osteogenic impairments.
慢性酒精摄入会增加骨吸收，减少骨形成。乙醇（EtOH）在骨骼中的主要病理成分是产生过量的活性氧（ROS）。ROS 生成的 NADPH 氧化酶-4（NOX4）被认为是导致大部分 EtOH 诱导的骨形成抑制的原因。在这里，13 周龄雄性野生型（WT）和 NOX4 小鼠分别用高脂肪（35%）、Lieber-DeCarli 液体饮食喂养，并分别与不含 EtOH 的饲料进行配对喂养（PF），EtOH 占总热量的 30%，共喂养 12 周。微计算机断层扫描分析显示，与 PF 对照组相比，WT、EtOH 喂养的小鼠的小梁骨体积/总体积（BV/TV）百分比和皮质厚度明显降低。与 PF 相比，EtOH 喂养的 NOX4 小鼠的小梁骨 BV/TV 和小梁数量也减少（<0.05）。然而，NOX4 小鼠免受 EtOH 引起的皮质厚度降低的影响（<0.05），并免受皮质骨中胶原蛋白 1 和骨钙素 mRNA 表达降低的影响（<0.05）。在 WT 和 NOX4 椎骨中，EtOH 抑制了促进成骨细胞成熟的 Wnt 信号成分的表达。NOX4 在 EtOH 抑制成骨细胞分化中的作用进一步通过对 NOX4 而不是缺乏活性 NADPH 氧化酶-2 的 p47 小鼠的骨髓培养物中 EtOH 抑制成骨细胞生成的保护作用来证明。然而，与 WT 培养物相比，NOX4 小鼠的骨髓培养物形成的成骨细胞集落较少（<0.05），这表明 NOX4 在维持间充质祖细胞群体中起作用。这些数据表明，NOX4 缺失部分可防止 EtOH 对成骨细胞分化的影响，但可能使骨骼易发生成骨缺陷。
